The present invention involves an improved process for resolving homopyrrolidone carboxylic acid (HPCA), i.e., 6-oxo-2-piperidinecarboxylic acid. The process allows direct and highly selective crystallization of pure S-HPCA dehydroabietylammonium salt [S-HPCA.DAA] from a solution containing the acid and dehydroabietylamine (DAA) in a solvent system consisting of dimethylformamide, cyclohexane and acetone.
The S-enantiomer of HPCA has been prepared via resolution of R,S-HPCA by formation of diastereomeric quinine salts followed by subsequent fractional crystallization and recovery of the individual enantiomers (U.S. application Ser. No. 753,242).
Conventionally, resolution of carboxylic acids via formation of diastereomeric salts requires (1) purification of the salts; (2) repeated fractional crystallizations with or without seeding to enrich the desired diastereoisomer; and (3) recovery of the resolved acid from the corresponding diastereoisomer salt. Very often, a different solvent is required for each step and the diminished yield after each step makes the cost of the process formidably high and industrially impractical.
The improved process of this invention is distinguishable from the conventional kinetic resolution method because it is virtually a one-step reaction-resolution process which affords a desired diastereoisomer salt without any need for fractional crystallization. The S-HPCA.DAA salt is the only diastereoisomer that crystallizes from the solvent system. Furthermore, none of the conventionally required purification of crude salts; enrichment of the desired isomer; seeding; or final purification is necessary, since the pure S-HPCA.DAA salt is directly crystallized from the crude reaction mixture. As a result, the improved resolution process is much shorter and simpler, and more economic than the conventional processes.